During vertebrate development, neural crest (NC) cells migrate from the dorsal neural tube and generate a wide variety of cell types throughout the embryo including neurons, glia, melanocytes, smooth muscle, cartilage and bone. The formation of NC progenitors has been extensively studied, yet molecules controlling NC multipotency and self-renewal and factors mediating cell-intrinsic distinctions between multipotent versus fate-restricted progenitors are poorly understood. As part of my thesis work, I show that the transcription factor Foxd3 mediates a fate restriction choice for multipotent NC progenitors with loss of Foxd3 biasing NC toward a mesenchymal fate. Neural derivatives of NC were lost in Foxd3 mutant mouse embryos, whereas abnormally-fated NC-derived vascular smooth muscle cells were ectopically located in the aorta. Cranial NC defects were associated with precocious differentiation towards osteoblast and chondrocyte cell fates, and individual mutant NC from different anterior-posterior regions underwent fate changes, losing neural and increasing myofibroblast potential.
During development of the enteric nervous system (ENS) Foxd3 expression is maintained in NC progenitors and glia. Using a novel Ednrb-iCre transgene to delete Foxd3 after NC migrate into the midgut, I demonstrated a late temporal requirement for Foxd3 during ENS development. Fate mapping in Foxd3 mutant embryos revealed a reduction of ENS progenitors throughout the gut and loss of Ednrb-iCre lineage cells in the distal colon. Although mutant mice were viable, defects in ENS patterning were associated with severe reduction of glial cells derived from the Ednrb-iCre lineage. Lineage and differentiation analysis suggested a compensatory population of Foxd3-positive progenitors that did not express Ednrb-iCre in mutant embryos. My findings highlight the roles played by Foxd3 during ENS development including proliferation of ENS progenitors, neural patterning, and glial differentiation.
Collectively, these data suggest Foxd3 functions as a critical regulator of NC fate potential and establish novel parallels between NC and other progenitor populations that depend on this functionally conserved stem cell protein to regulate multipotency and self-renewal.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03232011-141941 |
| Date | 07 April 2011 |
| Creators | Mundell, Nathan Andrew |
| Contributors | Joey V. Barnett, Patricia A. Labosky, Kendal S. Broadie, Ronald B. Emeson, Michelle Southard-Smith |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03232011-141941/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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